| First Author | Lacombe J | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 5 | Pages | 112500 |
| PubMed ID | 37171959 | Mgi Jnum | J:337581 |
| Mgi Id | MGI:7489486 | Doi | 10.1016/j.celrep.2023.112500 |
| Citation | Lacombe J, et al. (2023) Vitamin K-dependent carboxylation regulates Ca(2+) flux and adaptation to metabolic stress in beta cells. Cell Rep 42(5):112500 |
| abstractText | Vitamin K is a micronutrient necessary for gamma-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse beta cells lacking gamma-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced beta cell stress. In human islets, gamma-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a gamma-carboxylated ER-resident Ca(2+)-binding protein expressed in beta cells. Mechanistically, gamma-carboxylation of ERGP protects cells against Ca(2+) overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca(2+) entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca(2+) flux in beta cells and in their capacity to adapt to metabolic stress. |
